Preterm labor and its complications are major perinatal public health issues in developed societies today. They account for half of all infant deaths and three-quarters of long-term morbidity. They impose a heavy burden on the national economy, because of the high costs of special care in both the neonatal period and over the life-span of survivors. Many survivors also have diminished quality of life because of physical damage resulting directly from prematurity.
The rationale of all current empirical methods of managing preterm labor is to attempt tocolysis with the aim of reducing the frequency and force of uterine contractions and delaying birth. Drug therapy for such tocolysis includes Mg.sup.+ -infusion, inhibitors of prostaglandin synthesis (e.g., indomethacin), .beta.-adrenergic agonists (e.g., ritodrine, tertbutaline), and calcium-channel blocking agents (e.g., nifedipine). Although each of these alternatives can temporarily reduce premature contractions, none of them has proven to be effective in substantially delaying parturition. The pharmacodynamic mechanisms or these therapies in relation to the management of preterm labor are discussed briefly below:
In visceral smooth muscles, activation of .beta.-adrenergic receptors often leads to hyperpolarization and relaxation. Underlying this phenomenon is a G.sub.s protein-mediated and protein kinase A-catalyzed increase in the openings of a class of large-conductance Ca.sup.2+ -activated K.sup.+ channel.sup.20. In the late-pregnant uterine myocyte, however, the functional expression of this class of K.sup.+ channels is depressed.sup.8. So, it is unclear how effective an agent which works via such K.sup.+ channels would be in modulating excitability of the myometrium. Moreover, .beta.-adrenergic agonists also stimulate the synthesis of prostaglandins.sup.21. Perhaps because of these reasons, ritodrine is effective for only a few days, and does not affect the pregnancy outcome.sup.5. Moreover, it can produce cardiovascular side-effects in some recipients..sup.5
The use of calcium-channel blocking agents for uterine tocolysis is now being tested, but it is too early for statistically evaluable results. However, from physiological and pharmacological considerations, such agents are less than ideal. The primary concern militating against their use is that there are no significant demonstrated differences between the L-type calcium channels in the myometrium.sup.7 and those in many other types of smooth muscles, including various vascular smooth muscles. Unless an agent can selectively block the myometrial calcium channels, it will produce side-effects on a wide range of other tissues. For similar reasons of a lack of specificity, inhibitors of prostaglandin synthesis, although capable of inducing myometrial tocolysis, are liable to produce side-effects.sup.6.
Under physiological conditions, contractions in muscular tissues is the end result of a sequence of processes which begins with the generation of electrical signals in the cellular surface membrane, influx or release from stores of calcium ions, activation and cross-bridge formation between actin and myosin filaments. In most mammalian visceral smooth muscles, the electrical signals, the action potentials, are based on voltage-gated calcium channels.
Unique among them, small tissue-level multicellular strips of uterine smooth muscle have been shown to produce both sodium and calcium currents. C.Y. Kao et al., Ionic currents in the uterine smooth muscle, J. Physiology (London) 246: 1-36, 1975. In freshly dissociated single myocytes from the uterine muscle, both voltage-gated sodium channels and voltage-gated calcium channels have been demonstrated. The functional expression of the myometrial sodium channel is under the control of estrogen. The coexistence of the two different types of channels has been demonstrated in the uterine myocytes of rats (freshly dissociated cells.sup.7,10,11), rabbits (freshly dissociated, unpublished observations of S. Y. Wang and C. Y. Kao), and women (freshly dissociated, unpublished observations of S. Y. Wang, C. Y. Kao and D. Nanda; tissue-cultured.sup.12). Significantly, in the rat uterine myocytes, the ratio of the peak sodium/calcium currents changes during the course of pregnancy, such that the contribution of the sodium channel in generating action potentials progressively increases towards term.sup.7,13. In the pregnant rat, the sodium channels appear to be pivotal in the generation of fast repetitive action potentials to enable excitation of the entire uterus.sup.7.
U.S. Pat. Nos. 5,091,387; 5,095,003; 5,198,463; 5,175,159; 5,204,349 and 5,225,528 describe oxytocin antagonists as useful in the treatment of preterm labor. (Oxytocin is a hormone which stimulates the frequency and force of uterine muscle contractions). U.S. Pat. No. 5,242,947 describes polyamines and their use as ionic-channel regulating agents, but does not describe their use in the treatment of pre-term labor. None of these U.S. patents discusses lidocaine or its use to treat pre-term labor.
Inoue and Sperelakis (1991), Am. J. Physiol. 260: C658-C663, studied the changes in ionic channel densities over much of gestation, using the patch clamp method in freshly isolated smooth muscle cells of myometrium. They conclude that the fraction of cells which possess fast sodium channels increases during gestation and state that
t!hese results suggest that the role of fast Na.sup.+ channels in myometrial activity becomes more and more important as term approaches . . . . T!he fast Na.sup.+ current may be involved in spread of excitation.
See abstract and p. C661, col. 2. They further note that " t!he role of the fast Na.sup. + channel is not known" (p. C661, col. 2) and suggest that their increased number may result in faster propagation of excitation, and hence, more forceful contraction during parturition (p. C662, col. 1), but state that " f!urther experiments are necessary to clarify the physiological role of the fast Na.sup.+ channels in pregnant myometrial smooth muscle cells." (P. C662, col. 2).
Miyoshi et al. (1991), Eur J. Physiol. 419:386-393, applied the whole-cell voltage-clamp method to single smooth muscle cells prepared from pregnant rat myometrium (17-20 days of gestation). In a small number of preparations (in 2 out of 30 preparations) a tetrodotoxin ("TTX")-sensitive fast inward current was detected, suggesting that the channel for this current is equivalent to the Na.sup.+ channel in nerve cells. See abstract and p. 322, col. 1. These authors conclude that " t!his observation clearly indicates that the contribution of Na.sup.+ channels to the action potential in the physiological condition is extremely small, if any." See p. 332, col. 1.
Inoue et al. (1990), Am. J. Obstet. Gynecol. 162:1090-1098, studied the membrane properties of human pregnant myometrium with the conventional microelectrode and patch clamp methods. They state that their "results confirmed the importance of calcium and sodium ions for generation of action potential in human myometrium," even though they failed to record a sodium current. See p. 1097, col. 1.
Kao et al. (1989), J. Physiol. 418:20P, studied myocytes from 17-21 day pregnant rats with the whole-cell tight seal patch-clamp method. They reported recording sodium and calcium inward currents as well as outward currents.
Ohya and Sperelakis (1989), Am. J. Physiol. 257:C408-C412.sup.11 reported that TTX-sensitive fast Na.sup.+ channels existed in pregnant rat myometrium (day 18) by using the whole cell voltage-clamp method, but did not investigate the changes in this channel during gestation. They conclude that "the major ion channels in the cell membrane of pregnant rat uterus . . . are TTX-sensitive fast Na.sup.+ channels and dihydropyridine-sensitive slow Ca.sup.2+ channels". See abstract. They state that "the role of fast Na.sup.+ channels is unknown" but that "insertion of fast Na.sup.+ channels into the cell membrane during pregnancy, would allow for . . . faster propagation over the entire uterus . . ., as required for parturition." They conclude that "further study is required to clarify the role played, if any, of the fast Na.sup.+ current is uterine physiology." See p. C411, Col. 2.
Young and Herndon-Smith (1991), Am. J. Obstet. Gynecol. 164:175-181.sup.12, conducted voltage-clamp studies using the whole-cell patch clamp technique on single cells of cultured human uterine smooth muscle obtained from term pregnancies. A TTX-sensitive fast sodium channel was observed in the cultured human myocytes. The authors state that " t!he physiologic role of the sodium channel is not immediately apparent" (p. 179, col. 2) and further state that sodium channels "will not likely contribute to the rise of the action potential" (p. 180, col. 2).
Nakai and Kao (1983), Fed Proc 42:313.sup.13, reported in abstract form, using a multicellular preparation of pregnant rat myometrium, that the ratio of sodium current to calcium current increases as term approaches. They suggested "such a change could account for the faster rate of rise of the action potentials at term than in mid-pregnancy."
The present invention relates to the use of lidocaine and other Class I antiarrhythmic drugs to manage preterm labor. In particular, lidocaine has advantages over the drugs of the prior art in that it is expected to control the prematurely excitable and contracting human uterus and is also expected to have few or limited side-effects on the heart, vasculature, and the fetus, since the uterine muscle sodium channels are sensitive to concentrations of lidocaine too low to affect cardiac sodium channels, or potassium or calcium channels.
While some of the above-cited references speculate that the role of sodium channels may increase in importance as term approaches, the role of the sodium channels is acknowledged to be unknown. None of the above-cited references describe or suggest the use of a sodium channel affecter, such as lidocaine, as a potential tocolytic agent.